The compound 1,2,2,2-tetrafluoroethyl difluoromethyl ether (CF3CHFOCHF2), also known as desflurane, is an important inhalation anaesthetic. It is considered to be particularly safe due to its very low level of metabolism within the human body and is also particularly suited for administration for out patient procedures due to the rapid rate of patient recovery from anaesthesia.
There are several known methods for the preparation of desflurane. A process described in U.S. Pat. No. 3,897,502 for the preparation of desflurane involves direct fluorination of the ether, CF3—CH2—OCHF2 (2-difluoromethoxy-1,1,1-trifluoroethane) using elemental fluorine as the fluorinating agent. The reaction is carried out in a fluorinated solvent (Freon E3) using a mixture of 20% fluorine gas in argon, at −20° C. to −25° C. and over a long time to control the strong exothermic process. Due to the slow reaction time, low reaction temperature and the use of expensive and hazardous elemental fluorine in this process, it would be difficult to scale it up for commercial purposes. U.S. Pat. No. 6,054,626 partly addresses drawbacks associated with this process by disclosing a vapour phase process for producing desflurane. This process involves contacting CF3—CH2—OCHF2 (2-difluoromethoxy-1,1,1-trifluoroethane) in the vapour phase with a solid transition metal fluoride, preferably cobalt trifluoride as the fluorinating agent. The transition metal fluoride fluorinating agent can be regenerated in situ during the reaction by passing fluorine into the reaction zone such that cobalt trifluoride acts as a fluorine carrier. However, this process suffers from drawbacks such as relatively low yields of desflurane, formation of significant amounts of other polyfluorinated ether isomers and by-products. Moreover, this process also involves use of expensive and hazardous elemental fluorine.
The preparation of desflurane using isoflurane as the starting material and alkali metal fluorides as the fluorinating agents have been known. EP Patent No. 341,005B teaches a process for the manufacture of desflurane wherein a chlorofluoro organic ether, especially isoflurane is reacted with sodium fluoride or potassium fluoride at a temperature of 278° C. and an elevated pressure (500 psi) in the absence of a solvent. The process has to be operated at very high temperature and elevated pressure for a long period of time, resulting in significant capital cost. UK Patent Application No. GB 2,219,292A discloses a process for the manufacture of desflurane wherein isoflurane is reacted with an alkali metal fluoride (sodium fluoride, cesium fluoride, potassium fluoride) in an aprotic polar solvent (sulpholane) in the presence of a phase transfer catalyst (tetramethylammonium chloride) at a temperature of 210° C. This process also operates at a very high temperature. Moreover, both these processes are essentially batch processes.
An alternative method for producing desflurane from isoflurane using bromine trifluoride as a fluorinating agent has been disclosed in U.S. Pat. Nos. 4,762,856 and 5,015,781. Although the process gives a good yield and requires only a short reaction time, it employs bromine trifluoride, which poses significant handling problems and is expensive and therefore, not suitable for commercial manufacture.
Ger. Offen. DE 2361058 relates to a method of producing desflurane which involves initially chlorinating CF3—CHF—O—CH3 (1,2,2,2-tetrafluoroethyl methyl ether) to CF3—CHF—O—CHCl2 (1,2,2,2-tetrafluoroethyl dichloromethyl ether) and reacting the resulting chlorinated ether with anhydrous hydrogen fluoride using antimony pentachloride as a catalyst. This process suffers from the drawback that it may not be suitable for industrial scale up due to the lack of accessibility of the initial starting material. Moreover, this is a complex multistep process.
U.S. Pat. No. 5,026,924 describes a method of preparing desflurane by reacting isoflurane with excess hydrogen fluoride in the presence of an antimony pentachloride catalyst, alone or in combination with a small amount of antimony trichloride at relatively low temperature range of −10° C. to 30° C. This process suffers from the disadvantage that it is necessary to use a substantial molar excess of hydrogen fluoride in order to achieve acceptable yields and conversions. The use of excess fluorinating agent adds to the cost of preparation and necessitates the removal of excess hydrogen fluoride. U.S. Pat. No. 6,800,786 teaches a process for the manufacture of desflurane, which involves reacting isoflurane with optimum quantities of anhydrous hydrogen fluoride in presence of optimum quantity of antimony pentachloride to minimise the level of by-products formed and to increase the yield of desflurane. However, this process also results in difficult to separate by-products ultimately resulting in reduced yield of desflurane. A more recent International Patent Publication No. WO2006/055749 teaches the use of antimony pentafluoride instead of antimony pentachloride or mixed antimony chlorofluoride catalysts for reacting isoflurane and anhydrous HF while avoiding the necessity of using a molar excess of hydrogen fluoride. The reaction is carried out in a similar manner to the processes involving use of antimony pentachloride, but a lower molar ratio of hydrogen fluoride to isoflurane have been used. This process also claimed the benefits of a lower production of troublesome by-products. Although both processes employ antimony pentachloride or antimony pentafluoride catalysts which might improve the overall reaction conversion and yield as compared to using anhydrous HF alone, the reaction is either a batch or semi-continuous process involving disposal of the expensive catalyst after each batch.
Finally, a vapour phase process has been described in International Patent Publication No. WO 2006/076324 in which an isoflurane and hydrogen fluoride mixture in the vapour phase is passed over a chromia catalyst bed at 140° C. or 170° C. However, at the higher temperature a considerable amount of cleavage of the carbon-oxygen bond occurred to give about 10% of fragmentation products. At the lower temperature very little fragmentation occurred, but the conversion was only about 50%. This process hence has the disadvantage of a low conversion rate or a reduced yield due to fragmentation. Although the process is continuous it requires a higher hydrogen fluoride: isoflurane molar ratio resulting in higher hydrogen fluoride recycle or loss of hydrogen fluoride. Hence, there is a need to develop a vapour phase process which is efficient and can substantially eliminate the drawbacks of the existing processes.
The inventors of this invention have made possible a continuous vapor phase fluorination process for the preparation of desflurane by reacting optimum concentrations of isoflurane and a fluorinating agent such as anhydrous HF in presence of an efficient and easy to handle flourination catalyst. The vapor phase process minimizes the corrosion associated with liquid-phase catalytic fluorination especially those employing antimony halide catalysts. The process of the present invention enables continuous removal of desflurane product thereby minimizing co-production of byproducts and resulting in high conversion efficiency and yield of desflurane.